Support is requested for continuation of collaborative studies with colleagues at the Wistar Institute, in which toxin A chain conjugates with tumor specific monoclonal antibodies will be prepared and characterized. The A chains of diphtheria toxin and ricin toxin (DTA, RTA) will be disulfide crosslinked to anti-colorectal carcinoma and anti-melanoma monoclonal antibodies now available and others which are isolated during the period of the grant. The conjugates will be chemically characterized and assayed for toxic activity against a battery of antigen-bearing and control cell lines. Those conjugates which show significant toxicity will be prepared in quantity and tested in animals at the Wistar for nonspecific toxicity and suppression of tumorigenicity. Other effector moieties besides DTA and RTA will be examined with the goal of constructing more potent chimeric toxins. Such effectors include (i) chain termination fragments of DT containing DTA plus various portions of B; (ii) chemically modified forms of whole diphtheria toxin; and (iii) plant proteins, such as gelonin, with activities resembling that of RTA. As an approach to elucidating possible roles of tumor-associated antigens in malignancy, antibody-directed chimeric toxins will be used as selective agents to isolate mutant clones lacking the corresponding antigen. Such clones will be tested for capacity to form tumors in animal models.